Tetrahydroquinoline derivatives

ABSTRACT

The invention provides 5,6,7,8-tetrahydroquinoline derivatives which are substituted at the 8-position by the group NHCSNHR 5  where R 5  is lower alkanoyl or aroyl. These compounds are intermediates for corresponding compounds where R 5  is hydrogen, such compounds being anti-ulcer agents. 
     This application is a continuation-in-part of our copending U.S. application Ser. No. 554,259 filed Feb. 28, 1975, now U.S. Pat. No. 3,991,065.

The invention relates to novel tetrahydroquinoline derivatives and toprocesses for preparing them.

The invention provides a compound of formula I ##STR1## andpharmaceutically acceptable acid addition salts thereof, wherein R¹, R²and R³ are the same or different and represent hydrogen, or lower alkylor 1-6 carbon atoms, R⁴ represents hydrogen or substitution at the 5, 6or 7-position by lower alkyl of 1-6 carbon atoms, X is NHCSNHR⁵ where R⁵is lower alkanoyl or aroyl, with the proviso that when any two of R¹, R²and R³ are lower alkyl and are on adjacent carbon atoms then they areselected from normal and secondary alkyl groups.

When any of R¹, R², R³ or R⁴ is lower alkyl radical it has from 1 to 6carbon atoms and may have a straight or branched chain, e.g. methyl,ehtyl, n-, and iso-propyl and n-, s- and t-butyl, R⁴ may be agem-dimethyl group.

A preferred group of compounds have formula Ia ##STR2## where R ishydrogen or lower alkyl of 1-6 carbon atoms and R⁵ is lower alkanoyl of2-7 carbon atoms, benzoyl or halobenzoyl.

Particularly preferred compounds of formula I are those in which atleast one or more of R¹, R², R³ and R⁴ is methyl and the others arehydrogen.

Compounds of formula I wherein X is NHCSNHR⁵, wherein R⁵ is loweralkanoyl or aroyl are intermediates for corresponding compounds offormula I where R⁵ is hydrogen. These compounds are anti-ulcer agentswhich possess anti-ulcer activity in the test of Brodie and Hanson (seebelow) and sometimes anti-secretory or gastric anti-histamine activityin the test of Shay et al -- see below.

The compounds of formula I and Ia can form acid addition salts withinorganic acids e.g. hydrochloric, hydrobromic, sulphuric or nitricacids, or organic acids, e.g. citric, fumaric, maleic or tartaric acids.These acid addition salts are included in the invention.

In the compounds of formula I and Ia the carbon atoms to which X isattached is asymmetric. Consequently, the compounds can exist inoptically active d and l forms. These optically active forms and theracemates are included in the invention. The optically active forms maybe separated by standard techniques.

The preferred process for preparing compounds of formula I wherein X isNHCSNHR⁵ and R⁵ is aroyl or alkanoyl comprises reacting a compound offormula I wherein X is amino with an isothiocyanate of formula R⁵ NCSwherein R⁵ is as just defined.

The products wherein R⁵ is aroyl or alkanoyl are useful intermediatesfor preparing corresponding compounds wherein R⁵ is hydrogen. Thus aprocess for preparing compounds of formula I wherein X is NHCSNH₂comprises hydrolysing a corresponding compound of formula I wherein X isNHCSNH Acyl.

When R⁵ is aroyl it may be a benzoyl or substituted benzoyl radical e.g.halobenzoyl, such as chlorobenzoyl. When R⁵ is lower alkanoyl it mayhave from 2 to 7 carbon atoms examples being acetyl, propionyl, butyryl,and hexanoyl.

The hydrolysis of a compound where R⁵ is aroyl or lower alkanoyl may becarried out by treatment with a suitable base e.g. an alkali or alkalineearth metal hydroxide. Conveniently, sodium or potassium hydroxide maybe used.

The starting compounds of formula I wherein X is amino may be preparedby treatment of corresponding compounds of formula I wherein X is chloroor bromo with ammonia in a lower alkanol, e.g. methanol or ethanol.

The compounds of formula I wherein X is chloro or bromo are either knowncompounds or if novel may be prepared by methods analogous to thepreparation of known compounds e.g. by treatment of a correspondingcompound of formula I wherein X is hydroxy with thionyl chloride orphosphorus trichloride or tribromide, or by treatment of an N-oxide of acompound of formula I wherein X is hydrogen with an alkyl sulphonylhalide e.g. Me SO₂ Cl.

The starting materials wherein X is hydroxy are either known compoundsor if novel may be prepared by methods known for analogous compoundse.g. by formation of the N-oxide of a compound of formula I, wherein Xis hydrogen with hydrogen peroxide followed by acylation of the N-oxideand hydrolysis to give the compound of formula I wherein X is hydroxy.

A further method for preparing the compounds of formula I wherein X isamino comprises reducing a corresponding oxime of formula I, wherein Xis = NOH. The oximes may be prepared by treatment of a correspondingcompound of formula I, wherein X is oxo with hydroxylamine or bytreatment of a corresponding compound of formula I wherein X is hydrogenwith isoamyl nitrite in the presence of butyl lithium.

The compounds of formula I, wherein X is NHCSNHR⁵ wherein R⁵ ishydrogen, are anti-ulcer agents which display anti-ulcer activity in thetest of Brodie and Hanson, and sometimes anti-secretory or gastricanti-histamine activity. Anti-ulcer activity is determined by the methodof Brodie and Hanson, J. Applied Physiology, 15, 291, 1960.

Anti-secretory activity and gastric anti-histamine activity aredetermined by the method of H. Shay, D. Sun and H. Greenstein,Gastroenterology 1954, 26, 906-13. Activity in any one of the abovetests denotes an anti-ulcer agent.

The invention is illustrated by the following Examples. Temperatures arein ° C.

EXAMPLE 1 8-Hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline

3-Methyl-5,6,7,8-tetrahydroquinoline (50 g.) was dissolved in glacialacetic acid (180 ml.) and the solution treated with 30% hydrogenperoxide (70 ml.) and heated at 80° C for 20 hours. The solvent wasremoved in vacuo and the residual oil diluted with water (25 ml.) andre-evaporated. The resulting oil was dissolved in chloroform (100 ml.),washed with aqueous sodium carbonate (2 × 25 ml.), saturated brine (2 ×25 ml.), dried (MgSO₄) and the solvent removed in vacuo to give3-Methyl-5,6,7,8-tetrahydroquinoline-1-oxide (60 g.) as a pale yellowsolid which was used without purification. The N-oxide (60 g.) wasdissolved in acetic anhydride (120 ml.) and added to boiling aceticanhydride (120 ml.) and the mixture heated at reflux for 30 minutes. Thesolvent was removed in vacuo and the residual oil was treated with 10%hydrochloric acid (700 ml.) and the solution heated on a steam bath for2 hours. The cooled reaction mixture was adjusted to pH 9.0 with sodiumhydroxide and extracted with ether (3 × 100 ml.). The combined etherealextracts were washed with saturated brine, dried (MgSO₄) and the solventremoved in vacuo. The resultant oil was distilled at 0.15 mmHg to give acolourless oil (22 g.) b.p. 70°-78° C which crystallised from n-hexaneto give 8-hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline as colourlessneedles m.p. 58° C.

(Found: C, 73.7; H, 8.2; N, 8.3. C₁₀ H₁₃ NO requires: C, 73.6; H, 8.0;N, 8.6%).

EXAMPLE 2 8-Chloro-3-methyl-5,6,7,8-tetrahydroquinoline

The 8-hydroxy product of Example 1 (15 g.) was added portionwise tothionyl chloride (33 g.) at 0° C and the mixture stirred at 0° C for 1hour and heated at reflux for an additional 2 hours. The solvent wasremoved in vacuo and the residual oil heated at reflux for 1 hour withethanol (15 ml.) to remove excess thionyl chloride. The resultantprecipitate was recrystallised from ethanol-ether to give8-chloro-3-methyl-5,6,7,8-tetrahydroquinoline hydrochloride ascolourless needles (17.4 g.) m.p. 177° C.

(Found: C, 55.3; H, 6.1; N, 6.5. C₁₀ H₁₂ ClN.HCl requires: C, 55.1; H,6.0; N, 6.4%).

EXAMPLE 3 8-Amino-3-methyl-5,6,7,8-tetrahydroquinoline

The 8-chloro product of Example 2 (17 g.) was dissolved in methanolsaturated with ammonia (400 ml.) and heated at 80° in a stainless steelbomb for 24 hours. The solvnet was removed in vacuo and the residual oiltiturated with anhydrous ether (3 × 50 ml.) and the trituratesdiscarded. The oily solid was dissolved in water the pH adjusted to 9.0with sodium carbonate and extracted with ether (3 × 150 ml.). Thecombined extracts were dried (MgSO₄) and the solvent removed in vacuo togive a pale yellow oil (5.5 g.). A sample (500 mg) was dissolved inanhydrous ether (25 ml.) and the solution treated with excess etherealhydrogen chloride and the resultant solid recrystallised frommethanol-ether to give 8-amino-3-methyl-5,6,7,8-tetrahydroquinolinedihydrochloride quarter hydrate as colourless needles m.p. 210° C.

(Found: C, 50.5; H, 6.9; N, 11.6. C₁₀ H₁₄ N₂.2HCl. 1/4H₂ O requires: C,50.2; H, 7.1; N, 11.7%).

EXAMPLE 48-Methylthiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline

The 8-amino product of Example 3 (free base) (3 g.) was dissolved inacetonitrile (30 ml.) and the solution treated with methylisothiocyanate(1.35 g.) and heated at reflux for 2 hours. The solvent was removed invacuo and the residual solid recrystallised from absolute ethanol togive the title compound as colourless needles (3 g.) m.p. 113° C.

(Found: C, 61.4; H, 7.3; N, 17.8. C₁₂ H₁₇ N₃ S requies: C, 61.2; H, 7.3;N, 17.9%).

The product displayed anti-ulcer, anti-secretory and gastricanti-histamine activity.

EXAMPLE 58-Benzoylthiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline

A solution of 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline (6 g.) inacetone (48 ml.) was treated with benzoylisothiocyanate (6 g.) and themixture heated at reflux for 45 minutes. The solvent was removed invacuo and the residual solid recrystallised from ethanol-ether to givethe title compound as colourless needles (7.2 g.) m.p. 168° C.

(Found: C, 66.5; H, 6.1; N, 13.0. C₁₈ H₁₉ N₃ OS requires: C, 66.4; H,5.9; N, 12.9%).

EXAMPLE 6 8-Thiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline

8-Benzoylthiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline (6 g.)was treated with a 10% sodium hydroxide solution (24 ml.) and themixture heated on a steam bath for 15 minutes. The cooled reactionmixture was adjusted to pH 1.0 with conc. HCl, filtered to removebenzoic acid and the filtrate adjusted to pH 10.0 with aqueous ammonia.The resultant solid was recrystallised from ethanol to give the hydrateof the title compound as colourless needles (4 g.). m.p. 114° C.

(Found: C, 55.3; H, 7.3; N, 17.2. C₁₁ H₁₅ N₃ S.H₂ O requires: C, 55.1;H, 7.3; N, 17.4%).

The product displayed anti-ulcer activity in the test of Brodie andHanson (loc cit) at 100 mpk and anti-secretory activity in the test ofShay et al (loc cit) at 30 mpk.

EXAMPLE 7 8-Chloro-3-methyl-5,6,7,8-tetrahydroquinoline

Methanesulphonyl chloride (1.62 ml.,0.02mol.) was added dropwise at 0° Cto 3-methyl-5,6,7,8-tetrahydroquinoline-1-oxide (1.63 g., 0.02 mol.) andthe mixture stirred at 0° C for 2 hours and at 80° C for 2.5 hours. Thecooled reaction mixture was diluted with water (5 ml.) and the pHadjusted to 9.0 with sodium carbonate and the solution extracted withethyl acetate (3 × 25 ml.).

The combined extracts were dried (MgSO₄) and the solvent removed invacuo to give a yellow oil (1.2 g.). A sample (500 mg.) was dissolved inanhydrous ether and treated with excess ethereal hydrogen chloride andthe resultant solid recrystallised from ethanol-ether to give the titlecompound as colourless needles m.p. 177° C identical to authenticmaterial.

EXAMPLE 8 3-Methyl-8-oximino-5,6,7,8-tetrahydroquinoline

8-Hydroxy-3-methyl-5,6,7,8-tetrahydroquinoline (42.5g) in methylenechloride (21/21) was stirred at room temperature with manganese dioxide(425g) for 16 hours. The manganese dioxide was removed by filtration andwashed with methylene chloride. The filtrate was evaporated to drynessunder reduced pressure and the residue was distilled to give5,6-dihydro-3-methyl-7H-quinolin-8-one (30g) b.p. 142°-4° C. at 0.5mm.

The quinoline (30g), hydroxylamine hydrochloride (14g), sodium hydroxide(9g), ethanol (165ml) and water (65ml) were stirred and refluxed for 2hours. Water (100ml) was added and the product was allowed tocrystallise overnight. The crystals were removed by filtration andwashed with water and dried to give3-methyl-8-oximino-5,6,7,8-tetrahydroquinoline (27.5g) mp 188° C.

Found: C,68.5; H,6.9; N,15.4, C₁₀ H₁₂ N₂ O requires C,68.2; H,6.9;N,15.1%.

EXAMPLE 9 8-Amino-3-methyl-5,6,7,8-tetrahydroquinoline

3-Methyl-8-oximino-5,6,7,8-tetrahydroquinoline (27.5g) was dissolved inethanol (550ml) and 2N sodium hydroxide solution (550ml) was added. Thesolution was stirred vigorously and nickel aluminium alloy (41.3g) wasadded portionwise over 30 mins and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was filtered throughkieselguhr and the filter cake washed with ethanol and water. Thecombined filtrate was evaporated to low bulk under reduced pressure andthe residue was extracted with chloroform. The chloroform solution wasdried (MgSO₄) and evaporated under reduced pressure. The residue wasdissolved in ether (500ml) and filtered and ethereal HCl was added tothe filtrate till no more precipitate formed. The solid was removed byfiltration and recrystallised from methanol/ether to give8-amino-3-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (26.2g).

EXAMPLE 10 4-Methyl-8-oximino-5,6,7,8-tetrahydroquinoline

Following the procedure of Examples 1 and 84-methyl-5,6,7,8-tetrahydroquinoline may be converted to4-methyl-8-oximino-5,6,7,8-tetrahydroquinoline.

EXAMPLE 11 8-Amino-4-methyl-5,6,7,8-tetrahydroquinoline

Following the procedure of Example 94-methyl-8-oximino-5,6,7,8-tetrahydroquinoline may be converted to8-amino-4-methyl-5,6,7,8-tetrahydroquinoline which may be obtained asthe hydrochloride in the manner of Example 9.

EXAMPLE 128-Methylthiocarbamoylamino-4-methyl-5,6,7,8-tetrahydroquinoline

The title compound may be obtained from the 8-amino compound of Example11 by following the procedure of Example 4.

EXAMPLE 13 3,7,7-Trimethyl-8-oximino-5,6,7,8-tetrahydroquinoline

3,7,7-Trimethyl-5,6,7,8-tetrahydroquinoline may be converted to thetitle compound by following the procedure of Examples 1 and 8.

EXAMPLE 14 8-Amino-3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline

The oxime of Example 13 may be converted to the title compound by theprocedure of Example 9.

EXAMPLE 158-Methylthiocarbamoylamino-3,7,7-trimethyl-5,6,7,8-tetrahydroquinoline

The title compound may be prepared by treating the amino compound ofExample 14 with methylisothiocyanate according to the procedure ofExample 4.

EXAMPLE 16 2-Ethyl-8-oximino-5,6,7,8-tetrahydroquinoline

2-Ethyl-5,6,7,8-tetrahydroquinoline may be converted to the titlecompound by following the procedures of Examples 1 and 8.

EXAMPLE 17 8-Amino-2-ethyl-5,6,7,8-tetrahydroquinoline

The product of Example 16 may be converted to the title compound byfollowing the procedure of Example 9.

EXAMPLE 182-Ethyl-8-methylthiocarbamoylamino-5,6,7,8-tetrahydroquinoline

The amino compound of Example 17 may be converted to the title compoundby treatment with methylisothiocyanate according to the procedure ofExample 4.

EXAMPLE 19 2-n-Butyl-8-oximino-5,6,7,8-tetrahydroquinoline

2-n-Butyl-5,6,7,8-tetrahydroquinoline may be converted to the titlecompound following the procedures of Examples 1 and 8.

EXAMPLE 20 8-Amino-2-n-butyl-5,6,7,8-tetrahydroquinoline

The 8-oxime of Example 19 may be converted to the 8-amino title compoundby the procedure of Example 9.

EXAMPLE 212-n-Butyl-8-methylthiocarbamoylamino-5,6,7,8-tetrahydroquinoline

The product of Example 20 may be converted to the title compound of theprocedure of Example 4.

EXAMPLE 22 8-Oximino-2-phenyl-5,6,7,8-tetrahydroquinoline

2-Phenyl-5,6,7,8-tetrahydroquinoline may be converted to the titlecompound following the procedures of Examples 1 and 8.

EXAMPLE 23 8-Amino-2-phenyl-5,6,7,8-tetrahydroquinoline

The 8-oxime product of Example 22 may be converted to the title compoundfollowing the procedure of Example 9.

EXAMPLE 248-Methylthiocarbamoylamino-2-phenyl-5,6,7,8-tetrahydroquinoline

The 8-amino-compound of Example 23 may be treated withmethylisothiocyanate to give the title compound following the procedureof Example 4.

EXAMPLE 25 Following the procedure of Examples 1 and 8 the indicated5,6,7,8-tetrahydroquinolines may be converted to the corresponding 8oximes.

    ______________________________________                                        5,6,7,8-tetrahydroquinoline (THQ) derivative                                  Starting material                                                                            Final Product (THQ)                                            ______________________________________                                        3,4-dimethyl--THQ                                                                            3,4-dimethyl-8-oximino--THQ                                    3,5-dimethyl--THQ                                                                            3,5-dimethyl-8-oximino--THQ                                    3,6-dimethyl--THQ                                                                            3,6-dimethyl-8-oximino--THQ                                    2,4-dimethyl--THQ                                                                            2,4-dimethyl-8-oximino--THQ                                    3-n-butyl--THQ 3-n-butyl-8-oximino--THQ                                       3-n-pentyl--THQ                                                                              8-oximino-3-n-pentyl--THQ                                      3,7-dimethyl--THQ                                                                            3,7-dimethyl-8-oximino--THQ                                    5-n-butyl-3-methyl--THQ                                                                      5-n-butyl-3-methyl-8-oxi-                                                     mino--THQ                                                      3-methyl-6-isopropyl--THQ                                                                    3-methyl-8-oximino-6-isopropyl--                                              THQ                                                            4-n-hexyl--THQ 4-n-hexyl-8-oximino--THQ                                       5-methyl--THQ  5-methyl-8-oximino--THQ                                        6-ethyl--THQ   6-ethyl-8-oximino--THQ                                         7-n-propyl--THQ                                                                              8-oximino-7-n-propyl--THQ                                      ______________________________________                                    

EXAMPLE 26

Following the procedure of Example 9 the indicated 8-oximes may beconverted to the indicated 8-amino compounds which in turn may beconverted to the indicated8-methylthiocarbamoylamino-5,6,7,8-tetrahydroquinolines by the procedureof Example 4.

    __________________________________________________________________________    5,6,7,8-tetrahydroquinoline (THQ) Derivative                                                         8-methylthiocarb-                                      starting material                                                                         8-amino-THQ                                                                              amoyl--THQ                                             __________________________________________________________________________    3,4-dimethyl-8-                                                                           8-amino-3,4-                                                                             3,4-dimethyl-8-methyl-                                 oximino--THQ                                                                              dimethyl--THQ                                                                            thiocarbamoylamino--THQ                                3,5-dimethyl-8-                                                                           8-amino-3,5-                                                                             3,5-dimethyl-8-methyl-                                 oximino--THQ                                                                              dimethyl--THQ                                                                            thiocarbamoylamino--THQ                                3,6-dimethyl-8-                                                                           8-amino-3,6-                                                                             3,6-dimethyl-8-methyl-                                 oximino--THQ                                                                              dimethyl--THQ                                                                            thiocarbamoylamino--THQ                                2,4-dimethyl-8-                                                                           8-amino-2,4-                                                                             2,4-dimethyl-8-methyl-                                 oximino--THQ                                                                              dimethyl--THQ                                                                            thiocarbamoylamino--THQ                                3-n-butyl-8-                                                                              8-amino-3-n-                                                                             3-n-butyl-8-methyl-                                    oximino--THQ                                                                              butyl--THQ thiocarbamoylamino--THQ                                3-n-pentyl-8-                                                                             8-amino-3-n-                                                                             8-methylthiocarbamoyl-                                 oximino--THQ                                                                              pentyl--THQ                                                                              amino-3-n-pentyl--THQ                                  3,7-dimethyl-8-                                                                           8-amino-3,7-                                                                             3,7-dimethyl-8-methyl-                                 oximino--THQ                                                                              dimethyl--THQ                                                                            thiocarbamoylamino--THQ                                5-n-butyl-3-methyl-                                                                       8-amino-5-n-butyl-                                                                       5-n-butyl-3-methyl-8-                                  8-oximino--THQ                                                                            3-methyl--THQ                                                                            methylthiocarbamoyl-                                                          amino--THQ                                             3-methyl-8-oximino-                                                                       8-amino-3-methyl-                                                                        3-methyl-8-methylthio-                                 6-iso-propyl--THQ                                                                         6-isopropyl--THQ                                                                         carbamoylamino-6-iso-                                                         propyl--THQ                                            4-n-hexyl-8-oxim-                                                                         8-amino-4-n-hexyl--                                                                      4-n-hexyl-8-methylthio-                                ino--THQ    THQ        carbamoylamino--THQ                                    5-methyl-8-oximino--                                                                      8-amino-5-methyl--                                                                       5-methyl-8-methyl-                                     THQ         THQ        thiocarbamoylamino--THQ                                6-ethyl-8-oximino--                                                                       8-amino-6-ethyl--                                                                        6-ethyl-8-methylthio-                                  THQ         THQ        carbamoylamino--THQ                                    8-oximino-7-n-                                                                            8-amino-7-n-propyl                                                                       8-methylthiocarbamoyl-                                 propyl--THQ THQ        amino-7-n-propyl--THQ                                  __________________________________________________________________________

EXAMPLE 27

Following the procedure of Example 5 the following compounds may beprepared from 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline by replacingbenzoylisothiocyanate by the indicated isothiocyanate. The8-acyl-thiocarbamoyl compounds formed may be converted to8-thiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline by hydrolysisin the manner described in Example 6.

    ______________________________________                                        Isothiocyanate                                                                              8-acyl-thiocarbamoylamino-                                                    tetrahydroquinoline--(THQ)                                      acetylisothiocyanate                                                                        8-acetylthiocarbamoylamino-3-                                                 methyl--THQ                                                     propionylisothiocyanate                                                                     3-methyl-8-propionylthiocarb-                                                 amoylamino--THQ                                                 p-chlorobenzoylisothio-                                                                     8p-chlorobenzoylthiocarbamoylamino-                             cyanate       3-methyl--THQ                                                   ______________________________________                                    

We claim:
 1. A compound of formula I ##STR3## and pharmaceuticallyacceptable acid addition salts thereof, wherein R¹, R² and R³ are thesame or different and represent hydrogen, or a lower alkyl of 1-6 carbonatoms, R⁴ represents hydrogen or substitution at the 5, 6 or 7-positionby lower alkyl of 1-6 carbon atoms, R⁵ is lower alkanol of 2-7 carbonatoms, benzoyl or halobenzoyl with the proviso that when any two of R¹,R² and R³ are lower alkyl and are on adjacent carbon atoms then they areselected from normal and secondary alkyl groups.
 2. A compound asclaimed in claim 1 wherein R¹, R², R³ and R⁴ are selected from hydrogenand methyl.
 3. A compound as claimed in claim 1 which has the formula(Ia) ##STR4## wherein R⁵ is lower alkanoyl of 2-7 carbon atoms, benzoylor halobenzoyl, and R is hydrogen or lower alkyl of 1-6 carbon atoms. 4.A compound as claimed in claim 1, which is8-benzoylthiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline.